This invention relates to a technique for imparting freeze stability to chlorhexidine - containing mediciments. More specifically, this invention provides a method for preventing chlorhexidine gluconate from precipitating as the hydrochloride from chloride ion-containing aqueous solutions upon exposure to freezing conditions.
Chlorhexidine, which is 1, 1'-Hexamethylene-bis [5-pchlorophenyl biguanidine], is a widely used topical antiseptic. Because of solubility considerations, chlorhexidine is often used in the form of its gluconate salt especially in aqueous base formulations.
An example of a widely used, chlorhexidine containing formulation is that of ophthalmic solutions. Ophthalmic solutions in general may serve as a wetting agent in the eye, that is, an artificial tear material useful for the treatment of "dry-eye" or as a cleaning, lubricating and cushioning agent for the eye after an injury or therapeutic surgery. Ophthalmic solutions are also routinely used as a cleaning, lubricating and cushioning agent for both hard and gel-type contact lenses.
Typically, ophthalmic solutions are isotonic, buffered to the required pH, sterile and contain additives and mediciments to control viscosity, enhance wettability and provide bactericidal activity. Isotonicity usually is provided by sodium chloride or mixtures of sodium and potassium chloride. Hence, ophthalmic solutions will typically contain a relatively high chloride ion concentration. Patents which are considered to disclose representative ophthalmic solutions include U.S. Pat. Nos. 3,882,036 and 3,549,747 to Krezanoski et al and U.S. Pat. No. 3,767,788 to Rankin.
While chlorhexidine gluconate has sufficient solubility to effectively act as a topical antiseptic agent in aqueous preparations such as ophthalmic solutions, its rather low solubility is further affected by pH, ionic strength and temperature. In particular, it has been found that if a chloride-ion containing solution of chlorhexidine gluconate is subjected to freezing, the chlorhexidine tends to precipitate out in the form of chlorhexidine hydrochloride. This latter compound is far less soluble than is chlorhexidine gluconate and does not again dissolve. Hence, preparations containing chlorhexidine gluconate and chloride ion are effectively ruined by freezing. The solution becomes cloudy due to the dispersion of finely divided particles of chlorhexidine hydrochloride thus rendering it unacceptable for consumer use or sale.
Products such as ophthalmic solutions are often exposed to freezing temperatures during transport and warehouse storage. Additionally, since these preparations are often carried in luggage during travel, exposure to freezing temperatures can occur under these circumstances.